Search

BackgroundThe interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes.ObjectiveTo establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management.MethodsA multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care.ResultsThe task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA.ConclusionThe 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.

We investigated a Turkish family with multiple patients presenting with familial Mediterranean fever (FMF) and Behçet's disease (BD)-like manifestations. The index case and the two daughters with Behçet-like disease, were previously found to have a TNFAIP3 frameshift mutation. The high number of affected cases in this expanded family could be consistent with a dominantly inherited inflammatory disease, although some individuals had clinical features more consistent with recessively inherited FMF. We sequenced DNA from members of this family to determine whether the TNFAIP3 frameshift mutation and/or MEFV variants could explain this autoinflammatory disease pedigree.Patients were clinically diagnosed to have FMF or BD. Sanger sequence targeting TNFAIP3 exon 5 and MEFV exon 10 was carried out.The symptomatic mother of the index case and her affected maternal uncle had compound heterozygous FMF-associated MEFV mutations, p.Met680Ile and p.Arg761His. Two affected daughters of the maternal uncle also had compound heterozygous FMF-associated mutations, p.Met680Ile and p.Val726Ala. The index case and her two affected daughters had a TNFAIP3 frameshift mutation (c.799delG; p.Pro268Leufs*19), which is consistent with their HA20 diagnosis, and also carried a heterozygous MEFV p.Arg761His mutation.Autoinflammatory disease manifestations in a Turkish family with multiple affected cases could be explained by co-inheritance of pathogenic MEFV variants and a heterozygous HA20-associated mutation. FMF-associated p.Arg761His allele carried with the loss of function TNFAIP3 mutation by all three HA20 patients may contribute to their autoinflammatory phenotype and could also be responsible for their favourable response to colchicine.

Mutations in the type 1 TNF receptor (TNFR1) cause the autoinflammatory disorder TNF receptor-associated periodic syndrome (TRAPS), a disease characterized by recurrent fevers with inflammation. TRAPS-associated mutations in TNFR1 cause misfolding, retention in the ER, and loss of function as a conventional receptor, but instead initiate an intracellular signaling cascade that results in hyper-responsiveness to innate stimuli. Using mice engineered to have TRAPS-associated mutations in TNFR1, we examined the contents of peritoneal lavage fluid after intraperitoneal LPS injection in order to identify the pathogenic cell type. TNFR1 mutant mice have increased monocyte/macrophage infiltrates when compared to wild-type mice, but a similar number of recruited neutrophils. In mixed marrow chimeras, wild-type and TNFR1 mutant neutrophils were recruited similarly into the peritoneum after LPS injection, suggesting that there is no cell-intrinsic predisposition of TNFR1 mutant neutrophils to accumulate at sites of inflammation. In support of this, neutrophils from TRAPS patients and healthy donors migrate similarly in response to CXCL8. In contrast, we found that murine peritoneal macrophages from TNFR1 mutant mice produce higher amounts of two potent chemokines, CXCL1 and CXCL2, in response to LPS in vitro. These results suggest that enhanced chemokine secretion by monocytes, rather than hyper-responsiveness of neutrophils to these stimuli, is critical to the pathogenesis of TRAPS.

Mutations in the type 1 TNF receptor (TNFR1) cause an autosomal-dominantly inherited autoinflammatory disorder called TNF receptor-associated periodic syndrome (TRAPS). The disease is characterized by recurrent fevers with abdominal pain, migratory rash and inflammation. Patients also develop serositis, including peritonitis, as a manifestation of disease flares. TRAPS-associated mutant receptors do not traffic to the cell surface and accumulate in the endoplasmic reticulum, which may lead to abnormal TNF-independent receptor signaling and sustained inflammation. We examined the contents of peritoneal lavage fluid after intraperitoneal injection of LPS in TNFR1 mutant mice. Interestingly, heterozygous TNFR1 mutant mice had increased neutrophil infiltrates into the peritoneal cavity after LPS injection. We have investigated whether the exaggerated infiltration of neutrophils in mice with TNFR1 mutations is due to an intrinsic neutrophil abnormality or the release of more neutrophil-attracting chemokines by macrophages. We have performed chemotaxis experiments using neutrophils isolated from TRAPS patients as well as TNFR1 mutant mice, and measured the migratory responses of neutrophils toward chemoattractants and macrophage-derived supernatants. These results will provide insights into whether the intracellularly retained mutant TNFR1 may function to enhance local neutrophil accumulation in response to inflammatory stimuli in a cell autonomous manner.